Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Department of Orthodontics, College of Stomatology, North China University of Science and Technology, Tangshan, China.
PLoS One. 2021 Nov 18;16(11):e0249894. doi: 10.1371/journal.pone.0249894. eCollection 2021.
Inactivation of the tumor suppressor p53 (encoded by the Trp53 gene) is relevant for development and growth of different cancers, including osteosarcoma, a primary bone tumor mostly affecting children and young adolescents. We have previously shown that deficiency of the ribosomal S6 kinase 2 (Rsk2) limits osteosarcoma growth in a transgenic mouse model overexpressing the proto-oncogene c-Fos. Our initial aim for the present study was to address the question, if Rsk2 deficiency would also influence osteosarcoma growth in another mouse model. For that purpose, we took advantage of Trp53fl/fl mice, which were crossed with Runx2Cre transgenic mice in order to inactivate p53 specifically in osteoblast lineage cells. However, since we unexpectedly identified Runx2Cre-mediated recombination also in the thymus, the majority of 6-month-old Trp53fl/fl;Runx2-Cre (thereafter termed Trp53Cre) animals displayed thymic lymphomas, similar to what has been described for Trp53-deficient mice. Since we did not detect osteosarcoma formation at that age, we could not follow our initial aim, but we studied the skeletal phenotype of Trp53Cre mice, with or without additional Rsk2 deficiency. Here we unexpectedly observed that Trp53Cre mice display a unique accumulation of trabecular bone in the midshaft region of the femur and the humerus, consistent with its previously established role as a negative regulator of osteoblastogenesis. Since this local bone mass increase in Trp53Cre mice was significantly reduced by Rsk2 deficiency, we isolated bone marrow cells from the different groups of mice and analyzed their behavior ex vivo. Here we observed a remarkable increase of colony formation, osteogenic differentiation and proliferation in Trp53Cre cultures, which was unaffected by Rsk2 deficiency. Our data thereby confirm a critical and tumorigenesis-independent function of p53 as a key regulator of mesenchymal cell differentiation.
肿瘤抑制因子 p53（由 Trp53 基因编码）的失活与包括骨肉瘤在内的多种癌症的发生和发展有关，骨肉瘤是一种主要发生在儿童和青少年的原发性骨肿瘤。我们之前的研究表明，核糖体 S6 激酶 2（Rsk2）的缺失限制了过表达原癌基因 c-Fos 的转基因小鼠模型中骨肉瘤的生长。我们进行本研究的最初目的是为了探讨 Rsk2 缺失是否也会影响另一种小鼠模型中的骨肉瘤生长。为此，我们利用了 Trp53fl/fl 小鼠，它们与 Runx2Cre 转基因小鼠杂交，以特异性地在成骨细胞谱系细胞中失活 p53。然而，由于我们出人意料地发现了 Runx2Cre 介导的重组也发生在胸腺中，大多数 6 月龄的 Trp53fl/fl;Runx2-Cre（此后称为 Trp53Cre）动物出现了胸腺淋巴瘤，类似于 Trp53 缺陷型小鼠所描述的情况。由于我们在那个年龄没有检测到骨肉瘤的形成，因此我们无法按照最初的目的进行研究，但我们研究了 Trp53Cre 小鼠的骨骼表型，包括或不包括额外的 Rsk2 缺失。在这里，我们出人意料地观察到 Trp53Cre 小鼠在股骨和肱骨的中段区域出现了独特的小梁骨堆积，这与其先前作为成骨细胞生成的负调节剂的作用一致。由于 Rsk2 缺失显著减少了 Trp53Cre 小鼠的局部骨量增加，我们从不同组的小鼠中分离出骨髓细胞，并在体外分析它们的行为。在这里，我们观察到 Trp53Cre 培养物中的集落形成、成骨分化和增殖显著增加，而 Rsk2 缺失对其没有影响。我们的数据因此证实了 p53 作为间充质细胞分化的关键调节剂的肿瘤发生独立的关键和肿瘤发生独立的功能。
